Elevated blood cholesterol level is a major risk factor for the development of coronary heart disease, stroke and peripheral vascular disease. Of these, coronary heart disease has remained the leading cause of death in the United States and other affluent countries, in spite of recent advances in the management of the disease and understanding of the disease mechanism. It is understood that the underlying cause of the above-mentioned diseases is atherosclerosis, an insidious process of deposition of cholesterol and its esters, compounded with other materials, in characteristic plaques in the arterial wall.
Lowering blood cholesterol can reduce the risk of coronary heart disease (Stamler et al., JAMA 256:2823, 1986; The Lipid Research Clinics Coronary Primary Prevention Trial Results, I: Reduction in incidence of coronary heart disease. JAMA 251:351, 1984; The Lipid Research Clinics Coronary Primary Prevention Trial Results, II: The relation of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 251:365, 1984). In fact, each one percent reduction in blood cholesterol level is believed to result in approximately a two percent reduction in coronary heart disease rate (National Institutes of Health, Consensus Development Conference Statement. Vol. 5, No. 7).
Recommended methods for lowering blood cholesterol include reducing weight, increasing exercise, and altering diet by lowering cholesterol intake and substituting saturated fat with polyunsaturated fat. The effectiveness and drawbacks of several drugs that have been approved by FDA for use in the treatment of hypercholesterolemia have been recently reviewed (Blum et al., JAMA 261:3582, 1989).
Cholesterol and phospholipids are essential components of cellular organelles and membranes of animals. They are also major components of lipoproteins of the circulating blood. Their simultaneous occurrence in animal tissues indicates an affinity between molecules of phospholipids and cholesterol. This affinity has been utilized in the technology for preparing liposomes. Liposomes prepared from phospholipids, which are notoriously unstable, can be stabilized by the addition of cholesterol.
The affinity of phospholipids for cholesterol provides a basis for the hypothesis that phospholipids, when properly administered, could remove cholesterol from atherosclerotic plaques, and thus reduce the risk for coronary heart disease. Indeed, in experimental animals, intravenous administration of phospholipids has resulted in resolution of atherosclerotic lesions (Friedman et al., Proc. Soc. Exp. Biol. Med. 95:580, 1957; Howard et al., Atherosclerosis 14:17, 1971; Stafford et al., Artery 1(2):105, 1975). Extensive changes in serum lipoproteins in rabbits after intravenous injection of liposomes made of egg yolk phospholipids have been demonstrated. Such changes may have anti-atherogenic effects (Mendez et al., Lipids 23:961, 1988).
Although the above-described results suggest potential usefulness of phospholipids in the prevention and treatment of atherosclerosis, intravenous injection is an invasive method of drug delivery, and has objectionable features. The development of a more convenient method for delivering phospholipids, and thereby effecting a reduction in blood cholesterol levels, is needed. The present invention provides such method.